Chronic Obstructive Pulmonary Disease (COPD)
COPD is the overall term for a group of chronic conditions that are associated generally with the obstruction of lungs' airways. The disease may be accompanied by pulmonary hypertension (PH) but not necessarily. The term COPD refers in more detail to the following disorders: chronic bronchitis, bronchiectasis and emphysema.
Chronic bronchitis is an inflammatory disease that begins in the smaller airways within the lungs and gradually advances to larger airways. It increases mucus production in the airways and increases the occurrence of bacterial infections in the bronchial tree, which, in turn, impedes airflow. This chronic inflammation induces thickening of the walls of the bronchial tree leading to increasing congestion in the lungs that results in dyspnea. By definition, chronic bronchitis refers to a productive cough for at least three months of each of two successive years for which other causes have been ruled out.
Emphysema describes destruction of the lung architecture with enlargement of the airspaces and loss of alveolar surface area. Lung damage is caused by weakening and breaking the air sacs within the lungs. Several adjacent alveoli may rupture, forming one large space instead of many small ones. Larger spaces can combine into an even bigger cavity, called a bulla. As a result, natural elasticity of the lung tissue is lost, leading to overstretching and rupture. There is also less pull on the small bronchial tubes, which can cause them to collapse and obstruct airflow. Air that is not exhaled before the new inhale process gets trapped in the lungs, leading to shortage of breath. The sheer effort it takes to force air out of the lungs when exhaling can be exhausting.
Thus, the most common symptoms of COPD include shortness of breath, chronic coughing, chest tightness, greater effort to breathe, increased mucus production and frequent clearing of the throat. Patients are unable to perform their usual daily activities. Independent development of chronic bronchitis and emphysema is possible, but most people with COPD have a combination of the disorders. Both conditions decrease the lungs' ability to take in oxygen and remove carbon dioxide.
Long-term smoking is the most common cause of COPD, responsible for 80-90 to percent of all cases. Other risk factors are heredity, second-hand smoke, air pollution, and a history of frequent childhood respiratory infections. Cigarette smoking and other inhaled irritants plays a fundamental role in the pathogenesis of COPD, which affects as many as 8% of individuals in industrialized nations.
The inflammatory response in COPD involves a number of different cell types including mononuclear cells (macrophages), CD4+ and CD8+ T lymphocytes, neutrophils, which can be isolated from the lungs of patients with COPD. When activated, these cells induce mediators of inflammation and cytokines, such as interleukin (IL)-8, tumor necrosis factor-A (TNF-alpha), LTB4 which amplify the inflammatory response and may remodel lung architecture.
Moreover, there is excessive activity of proteases, and an imbalance between proteases and endogenous antiproteases. Corticosteroids do not appear to have any effect on the inflammation in COPD, with no changes in neutrophilic inflammation, reduction in inflammatory mediators, or proteases. There is a contrasting effect of corticosteroids on granulocytes, with a reduction in eosinophil survival but a prolongation of neutrophil survival. This is consistent with a failure of long-term corticosteroids to alter the progression of COPD, and indicates that new types of anti-inflammatory treatment need to be developed in the future.
Potential causes of pulmonary hypertension in COPD include emphysematous destruction of the capillary bed, remodeling of pulmonary vessels and hypoxic pulmonary vasoconstriction. In pulmonary arteries of subjects with COPD, thickening of the intimal layer is the most consistent morphological change produced by the proliferation of smooth muscle cells and the deposition of both elastic and collagen fibers.
Hypoxaemia is the principal factor determining endothelial dysfunction which leads to vasoconstriction. However endothelial dysfunction and intimal thickening may be present also in smokers with mild COPD who are not hypoxemic, indicating that factors other than hypoxemia, might be capable of producing vascular changes in smokers. The recent observation of an infiltration of inflammatory cells, mainly CD8+ T lymphocytes, in the adventitia of pulmonary arteries in smokers with COPD supports a possible role of these cells in inducing vascular alterations.
COPD is progressive and sometimes irreversible; there is currently no cure. The clinical development of COPD is typically described in three stages, as defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD):
GOLD 0: Lung function is normal. At risk. Chronic symptoms (cough, sputum).
GOLD I Mild: FEV1/FVC<70%, FEV1≧80% of predicted value. With or without chronic symptoms (cough, sputum).
GOLD II Moderate: FEV1/FVC<70%, 50%≦FEV1<80% PW. With or without chronic symptoms (cough, sputum).
GOLD III Severe: FEV1/FVC<70%, 30%≦FEV1<50% PW. With or without chronic symptoms (cough, sputum).
GOLD IV Very severe: FEV1/FVC<70%, FEV1<30% PW or FEV1<50% PW with chronic respiratory failure.
COPD prevalence increases with age, but there is a dramatic synergy with smoking such that smokers have higher COPD prevalence and mortality and lung function losses. A smoker is 10 times more likely than a non-smoker to die of COPD. When inhaled, the smoke paralyzes the microscopic hairs (cilia) lining the bronchial tree. Irritants and infectious agents caught in the mucus remain in the bronchial tree rather than being swept out by the cilia. This can inflame bronchial membranes, eventually resulting in chronic obstruction. Other indoor and outdoor air pollutants may damage the lungs and contribute to COPD.
Although there is no cure for COPD, medications that are prescribed for people with COPD include:
Fast-acting beta 2-agonists, such as salbutamol which can help to open narrowed airways;
Anticholinergic bronchodilators, such as ipratropium bromide, and theophylline derivatives, all of which help to open narrowed airways;
Long-acting bronchodilators, which help relieve constriction of the airways and help to prevent bronchospasm associated with COPD;
Inhaled or oral corticosteroids, that help reduce inflammation;
Antibiotics that are often given at the first sign of a respiratory infection to prevent further damage and infection in diseased lungs;
Expectorants that help loosen and expel mucus secretions from the airways, and may help make breathing easier;
Lung transplantation is being performed in increasing numbers and may be an option for people who suffer from severe emphysema;
Lung volume reduction surgery, shows promise and is being performed with increasing frequency;
Special treatments for al-antitrypsin (AAT) deficiency emphysema include AAT replacement therapy (a life-long process) are being evaluated;
Current research into COPD is also focusing on gene therapy to substitute for the AAT deficiency.
Newer developments describe the successful use of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in the treatment of COPD (WO 03/61680)
Cystic Fibrosis (CF)
Chronic lung disease is the chief cause of morbidity and mortality in CF. Bacterial colonization of the airways generally occurs within the first year or two after birth. Patients with CF have a predisposition to subsequent chronic colonization and infection with Pseudomonas aeruginosa, an organism whose presence in the CF lung is associated with progressive respiratory compromise. Infection is associated with an exuberant inflammatory response dominated by neutrophils and the potent inflammatory mediators that are released by activated neutrophils. An inexorable decrease in pulmonary function in the norm, leading eventually to death or to a need for lung transplantation. The experimental focus on the function of the CF gene CFTR in regulating epithelial ion transport has provided a compelling account of the pathogenesis of gastrointestinal disease in CF, as well as of the genesis of such CF-associated phenomena as high sodium chloride content in sweat. However, the examination of altered ion and water transport alone has failed to elucidate the path from gene to pathogenesis in the CF lung, something that has hindered therapeutic advances.
Indeed, it is notable that airway surface fluid is now believed to have normal concentrations of chloride and sodium in patients with CF. Another long-held pathogenic dogma regarding inflammation and infection in CF has also become suspect. It had been assumed that ineffective clearance of bacteria from the CF airway was primary to pathogenesis, leading secondarily to destructive chronic airway inflammation. It now seems possible that the causality is backwards in that formulation. There is a growing consensus that the CF airway is marked by an aberrant, exaggerated proinflammatory propensity that predates infection. In vivo studies using fetal human tracheal xenografts strongly suggest that this basal proinflammatory predisposition of the CF airway leads to the development of mucosal damage after infection, damage that is itself integral to subsequent persistent bacterial colonization of the airway. The airway inflammatory response in CF is persistently neutrophilic, marked by upregulation of neutrophil chemotactic mediators such as interleukin 8 (IL-8) and leukotriene B4 (LTB4); florid accumulation of neutrophils in the airways; and neutrophil activation, with release of toxic products such as neutrophil elastase. The initial inflammatory response to most bacterial stimuli, in the lung and elsewhere, is “acute”, that is, neutrophil dominant. However, in the absence of bacterial clearance there is normally modulation over time to less histotoxic, “chronic” inflammation, a shift marked by the presence and immunoregulatory to activity of monocytic cells and lymphocytes. An unusual feature of inflammation in the CF airway is that such modulation never takes place.
Pulmonary Arterial Hypertension, Primary Pulmonary Hypertension and Secondary Pulmonary Hypertension and Arterial Hypertension
Pulmonary arterial hypertension (PAH) is a fatal disease causing progressive right heart failure within three years after diagnosis. Recently, various pathophysiological changes associated with this disorder, including vasoconstriction, vascular remodelling (i.e. proliferation of both media and intima of the pulmonary resistance vessels), and in situ thrombosis have been characterized. Impairment of vascular and endothelial homeostasis is evidenced from a reduced synthesis of prostacyclin (PGI2), increased thromboxane production, decreased formation of nitric oxide and increased synthesis of endothelin. The intracellular free calcium concentration of VSMC of pulmonary arteries in PAH has been reported to be elevated.
Comparable to the pulmonary circulation, endothelial cells of the systemic circulation release both relaxing and contracting factors that modulate vascular smooth muscle tone and also participate in the pathophysiology of essential hypertension. Endothelium-dependent vasodilation is regulated primarily by nitric oxide but also by an unidentified endothelium-derived hyperpolarizing factor and by prostacyclin. Endothelium-derived contracting factors include endothelin-I, vasoconstrictor prostanoids, angiotensin II and superoxide anions. Under physiological conditions, there is a balanced release of relaxing and contracting factors. The balance can be altered in cardiovascular diseases such as hypertension, atherosclerosis, diabetes and other conditions, thereby contributing to further progression of vascular and end-organ damage. In particular, endothelial dysfunction leading to decreased bioavailability of nitric oxide impairs endothelium-dependent vasodilation in patients with essential hypertension and may also be a determinant for the premature development of atherosclerosis.
The therapy of pulmonary and arterial hypertension is unsatisfactory. Current therapy involves calcium cannel blockers and prostacyclins. Newer developments describe the application of vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in treatment of PPH, SPH and arterial hypertension. (see WO 02/43746).
Bronchiolitis Obliterans (BO)
Bronchiolitis obliterans is a chronic inflammatory disease characterised by a process centred in and around membranous and/or respiratory bronchioles with sparing of a considerable portion of the other parenchymal structures.
Bronchiolitis obliterans is a disease with airflow limitation that is not fully reversible.
The airflow limitation is usually progressive and is associated with an abnormal inflammatory response of the lungs. The prognosis is worse.
Bronchiolitis obliterans, the chronic rejection following lung transplantation, is an important factor limiting long term survival in lung graft recipients. As this chronic rejection responds only poorly to immunosuppression, re-transplantation remains the ultimate choice for patients with progressive disease. It is known from experimental and clinical studies that the T-helper (Th) 1 and the Th17 response play a critical role in the pathogenesis of BO. Thus, novel therapeutic strategies that target these immunologic reactions could be promising in the setting of BO. Vasoactive intestinal peptide (VIP) is a Th2 cytokine with anti-inflammatory properties, while Interferon (IFN)-γ is a Th1 cytokine with antifibrotic activity that inhibits the IL-17 production by Th17 cells. In the proposed project VIP and IFN-y will be used as a single or combination treatment to prevent BO development in an experimental model of orthotopic rat lung transplantation. The aim of this preclinical study is to study whether VIP or IFN-γ are effective in prevention/improvement of BO in the experimental model and thus could be introduced into clinical trials. Moreover, the aim of this study is to investigate the mechanisms of action of the proposed therapeutics, including the role of VIP in inducing regulatory T cells following transplantation and the role of IFN-γ in inhibiting inflammation promoted by IL-17.
Vasoactive Intestinal Peptide (VIP):
VIP is a 28 amino acid naturally occurring human peptide consisting of the following amino acid sequence (from N- to C-terminal):
(SEQ ID No. 1)His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg- Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn- Ser-Ile-Leu-Asn
The peptide is synthesized in various components of the central nervous system, e.g. specific brain regions like hippocampus and cortex as well as in the pituitary gland and peripheral ganglia. VIP is furthermore secreted by immune cells and by some neoplastic cells (e.g. pancreatic cancer). Healthy individuals exhibit low concentration of VIP (<40 pg/ml serum).
VIP is a widely distributed peptide hormone that mediates a variety of physiological responses including gastrointestinal secretion, relaxation of gastrointestinal vascular and respiratory smooth muscle, lipolysis in adipocytes, pituitary hormone secretion, and excitation and hyperthermia after injection into the central nervous system. Under physiologic conditions VIP acts as a neuroendocrine mediator. Importantly, VIP is a potent anti-inflammatory agent, as treatment with VIP significantly reduced incidence and severity of arthritis in an experimental model, completely abrogating joint swelling and destruction of cartilage and bone. VIP may elicit different biological and/or therapeutic effects some of them are described in WO 9106565, EP 0536741, U.S. Pat. No. 3,880,826, EP 0204447, EP 0405242, WO 9527496, EP 0463450, EP 0613904, EP 0663406, WO 9735561, and EP 0620008.
VIP receptor has been detected on airway epithelium of the trachea and the bronchioles. It is also expressed in macrophages surrounding capillaries, in connective tissue of trachea and bronchi, in alveolar walls, and in the subintima of pulmonary veins and pulmonary arteries.
As mentioned, VIP has a strong bronchorelaxing, vasorelaxing and anti-inflammatory effect. Therefore inhalation of VIP (or receptor selective analogous) is a promising approach for lung diseases. Although VIP in principal have been successfully used in clinical trials for the treatment of PPH, COPD and CF recently, these compounds unfortunately underlie considerable enzymatic degradation in bronchial tissue, especially when they are administered via inhalation.
Therefore, there is a need to provide peptides having these biological activities of VIP, which show, however, improved properties, especially in context with enhanced stability and enhanced therapeutic efficacy.